Altered Brain Development Research Articles

A human stem cell resource to decipher the biochemical and cellular basis of neurodevelopmental defects in Lowe syndrome.

ABSTRACTHuman brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS) is an X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1, which encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a ‘disease-in-a-dish’ model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.This article has an associated First Person interview with the first author of the paper.

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids.

Neurodevelopmental disorders (NDDs) are a collection of diseases with early life onset that often present with developmental delay, cognitive deficits, and behavioral conditions. In some cases, severe outcomes such as brain malformations and intractable epilepsy can occur. The mutations underlying NDDs may be inherited or de novo, can be gain- or loss-of-function, and can affect one or more genes. Recent evidence indicates that brain somatic mutations contribute to several NDDs, in particular malformations of cortical development. While advances in sequencing technologies have enabled the detection of these somatic mutations, the mechanisms by which they alter brain development and function are not well understood due to limited model systems that recapitulate these events. Human brain organoids have emerged as powerful models to study the early developmental events of the human brain. Brain organoids capture the developmental progression of the human brain and contain human-enriched progenitor cell types. Advances in human stem cell and genome engineering provide an opportunity to model NDD-associated somatic mutations in brain organoids. These organoids can be tracked throughout development to understand the impact of somatic mutations on early human brain development and function. In this review, we discuss recent evidence that somatic mutations occur in the developing human brain, that they can lead to NDDs, and discuss how they could be modeled using human brain organoids.

Sex-specific alterations of cortical morphometry in treatment-naïve patients with major depressive disorder.

Major depressive disorder (MDD) shows sex differences in terms of incidence and symptoms, but the neurobiological basis underlying these sex differences remains to be clarified. High resolution T1-weighted Magnetic Resonance Imaging (MRI) scans were obtained from 123 non-comorbid treatment-naïve individuals with MDD and 81 age-, sex-, andhandedness-matched healthy controls (HCs). MRI data were preprocessed with FreeSurfer software and four cortical measures were extracted: cortical thickness (CT), surface area (SA), cortical volume (CV), and local gyrification index (LGI). We tested for both sex-specific and sex-nonspecific patterns of cortical anatomic alterations. Regardless of sex, individuals with MDD showed significantly higher LGI in posterior cortex relative to HCs. Significant sex-by-group interactions were observed, and subsequent post-hoc analyses revealed that female individuals with MDD showed significantly lower SA in left ventrolateral prefrontal cortex (vlPFC), lower CV in right rostromedial prefrontal cortex (rmPFC), and higher LGI in left visual cortex compared with sex-matched HCs, whereas the opposite patterns of significant effects were seen in male individuals with MDD relative to their sex-matched HCs. Thus, sex-nonspecific and specific morphometric differences from HCs were found in posterior cortex, while in PFC alterations were highly sex-specific early in the illness course. This may involve sex-specific alterations in brain development or processes related to illness onset. These findings highlight the presence and regional distribution of generalized as well as sex-specific alterations of brain neurobiology in MDD.

Cognitive control inhibition networks in adulthood are impaired by early iron deficiency in infancy

Iron deficiency, a common form of micronutrient deficiency, primarily affects children and women. The principal cause of iron deficiency is undernutrition in low-income countries and malnutrition in middle to upper income regions. Iron is a key element for myelin production, neuronal metabolism, and dopamine functions. Iron deficiency in early life can alter brain development and exert long-lasting effects. Control inhibition is an executive function that involves several brain regions, including the prefrontal cortex and caudate and sub-thalamic nuclei. Dopamine is the prevalent neurotransmitter underlying cognitive inhibition. We followed cohort study participants who had iron deficiency anemia in infancy as well non-anemic controls. At 22 years of age, the participants were subjected to functional magnetic resonance imaging (fMRI) to evaluate the correlation between functional connectivity and performance on an inhibitory cognitive task (Go/No-Go). We hypothesized that former iron deficient anemic (FIDA) participants demonstrate less strength in functional connectivity compared with controls (C). There were not significant group differences in the behavioral results in terms of accuracy and response time. A continuous covariate interaction analysis of functional connectivity and the Go/No-Go scores demonstrated significant differences between the FIDA and C groups. The FIDA participants demonstrated less strength in connectivity in brain regions related to control inhibition, including the medial temporal lobe, impairment in the integration of the default mode network (indicating decreased attention and alertness), and an increase in connectivity in posterior brain areas, all of which suggest slower circuitry maturation. The results support the hypothesis that FIDA young adults show differences in the connectivity of networks related to executive functions. These differences could increase their vulnerability to develop cognitive dysfunctions or mental disorders in adulthood.

Choline supplementation as an intervention for fetal alcohol spectrum disorders: A commentary.

It is estimated that in the U.S. alone, somewhere between 1-5% of births are affected by prenatal alcohol exposure. Prevalence estimates are even higher in other regions of the world, including South Africa. Prenatal alcohol exposure can disrupt development, leading to a range of effects referred to as fetal alcohol spectrum disorders (FASD). Of particular concern are alterations in brain development, which lead to lifelong challenges in motor, emotional, social, and cognitive domains. There is an urgent need to identify treatments that can reduce neuropathology and consequent behavioral alterations to improve quality of life in individuals exposed to alcohol prenatally.

Perinatal exposure to the thyroperoxidase inhibitors methimazole and amitrole perturbs thyroid hormone system signaling and alters motor activity in rat offspring

Disruption of the thyroid hormone system during development can impair brain development and cause irreversible damage. Some thyroid hormone system disruptors act by inhibiting the thyroperoxidase (TPO) enzyme, which is key to thyroid hormone synthesis. For the potent TPO-inhibiting drug propylthiouracil (PTU) this has been shown to result in thyroid hormone system disruption and altered brain development in animal studies. However, an outstanding question is which chemicals beside PTU can cause similar effects on brain development and to what degree thyroid hormone insufficiency must be induced to be able to measure adverse effects in rats and their offspring. To start answering these questions, we performed a perinatal exposure study in pregnant rats with two TPO-inhibitors: the drug methimazole (MMI) and the triazole herbicide amitrole. The study involved maternal exposure from gestational day 7 through to postnatal day 22, to MMI (8 and 16 mg/kg body weight/day) or amitrole (25 and 50 mg/kg body weight/day). Both MMI and amitrole reduced serum T4 concentrations in a dose-dependent manner in dams and offspring, with a strong activation of the hypothalamic-pituitary-thyroid axis. This reduction in serum T4 led to decreased thyroid hormone-mediated gene expression in the offspring’s brains and caused adverse effects on brain function, seen as hyperactivity and decreased habituation in preweaning pups. These dose-dependent effects induced by MMI and amitrole are largely the same as those observed with PTU. This demonstrates that potent TPO-inhibitors can induce effects on brain development in rats and that these effects are driven by T4 deficiency. This knowledge will aid the identification of TPO-inhibiting thyroid hormone system disruptors in a regulatory context and can serve as a starting point in search of more sensitive markers of developmental thyroid hormone system disruption.

In Utero MRI Identifies Impaired Second Trimester Subplate Growth in Fetuses with Congenital Heart Disease.

Our findings provide an early biomarker for brain maturational failure in fetuses with congenital heart disease, which may guide the development of future prenatal interventions aimed at reducing neurological compromise of prenatal origin in this high-risk population.

A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation

Human genetics have defined a new neurodevelopmental syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes intellectual disability, autism, ADHD, obesity, and brain anomalies is unknown. Here, we developed a Myt1l haploinsufficient mouse model that develops obesity, white-matter thinning, and microcephaly, mimicking common clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene-target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. Myt1l haploinsufficiency also results in behavioral anomalies, including hyperactivity, muscle weakness, and social alterations, with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.

VP31.07: Fetal neurosonographic assessment after maternal COVID‐19 infection during pregnancy

To assess the impact of COVID-19 during pregnancy in terms of fetal neurosonography (NSG) and its association with maternal severity and gestational age at infection. Multicentric prospective cohort study including singleton pregnant women with COVID-19 infection at 5 hospitals in Spain, from April 2020 to April 2021. Maternal infection was confirmed by clinical symptoms, nasopharyngeal PCR, or by serologic testing. Pregnancies were subdivided according to clinical severity of maternal COVID-19 disease according to NIH Classification. Fetal NSG was performed once COVID-19 symptoms ceased, at least 4 weeks after maternal infection. NSG was performed in 306 fetuses including 77 asymptomatic patients (26%), 195 mild COVID-19 disease (64%), and 32 moderate/severe COVID-19 disease (one critical, 10%). Maternal infection occurred in first trimester in 27% of cases, in second trimester in 53%, and in 19.4% during the third trimester. Gestational age at NSG was similar among groups [median 33 weeks (IQR: 32.2-35.1)]. No significant differences were observed in fetal corpus callosum or fetal cortical development, according to maternal severity of COVID-19 (table 1) or trimester at infection. Severity of maternal COVID-19 infection during pregnancy does not seem be associated with fetal neurosonographic abnormalities nor altered cortical brain development.

RETRACTED: Sexual orientation, neuropsychiatric disorders and the neurotransmitters involved

According to the neuro-hormonal theory, sexual orientation in humans develops in the womb under the influence of sex hormones. In this article, we review the evidence from basic research on the possible role of neurotransmitters on influencing sexual orientation. We show that pharmacological or genetically induced changes in neurotransmitter systems during development might, by hormone-mediated structural and functional brain changes, result in alterations in sexual preference in animal models. We propose that in humans this mechanism may contribute to the relationship between non-heterosexual orientation and increased prevalence of neuropsychiatric disorders. Data to support this idea are reviewed. We suggest that altered neurotransmitter levels during development will increase the chance for both non-heterosexual differentiation of the brain and neuropsychiatric disorders. This possibility may have clinical implications, because medication given to a pregnant woman may, in this way, alter brain development of the fetus in a permanent way.

Dietary sialylated oligosaccharides in early-life may promote cognitive flexibility during development in context of obesogenic dietary intake

ABSTRACT Introduction: Oligosaccharides found in mammalian milk have shown the potential to alter brain development across multiple species. The diversity and concentration of these oligosaccharides is species-specific and varies greatly between individuals, thus understanding their role in cognitive development is warranted. We investigated the impact of early life dietary fucosylated/neutral or sialylated human milk oligosaccharides (HMO) on behaviours in tasks assessing anxiety, motivation, appetite, learning, and memory. Methods: Sixty-four female Göttingen minipigs were artificially reared from 2 weeks postnatal and provided milk replacers. The study used four groups: no additional oligosaccharides (Con), fucosylated and neutral oligosaccharides (FN, 4 g/L), sialylated oligosaccharides (SL, 0.68 g/L), or both FN and SL (FN + SL, 4 g/L) from 2 to 11 weeks postnatal. One reference group was sow-reared. Weaning occurred between 10 and 11 weeks postnatal, and thereafter an obesogenic diet was provided. Behavioral tasks were conducted over three periods: 1) 0–11 weeks; 2) 16–29 weeks; 3) 39–45 weeks. Tasks included a spatial holeboard task, open field task, exposure to a novel object, runway task, single-feed task, and home pen behaviour observation. Results: In the holeboard, the SL group demonstrated improved reference memory during reversal trials between 16-29 weeks. All groups demonstrated equivalent behavior in open field, novel object, runway, and single-feed tasks, as well as in their home pens (Ps > 0.05). Discussion: These results suggest that early life dietary intake of sialylated oligosaccharides may provide an improvement to cognition during the equivalent developmental stage of adolescence.

Timing-specific associations between income-to-needs ratio and hippocampal and amygdala volumes in middle childhood: A preliminary study.

It is well known that financial disadvantage is associated with alterations in brain development in regions critical to socioemotional well-being such as the hippocampus and the amygdala. Yet little is known about whether family income at different points in development is differentially associated with these structures. Furthermore, little is known about which environmental factors statistically mediate associations between income and subcortical structure. Using a longitudinal birth cohort and linear mixed-effects models, we identified associations between income-to-needs ratio (INR) at 6 timepoints throughout childhood and hippocampal and amygdala volumes at age 7-9 years (n=41; 236 INR measurements; 41 brain measurements). Mediation analysis identified environmental sequelae of income that statistically accounted for INR-brain associations. Lower INR prior to age 4 was associated with smaller hippocampal volumes, whereas lower INR prior to age 2 was associated with smaller right amygdala volume. These associations were mediated by unmet basic needs (e.g., food, housing). These findings delineate the temporal specificity of associations between income and hippocampal and amygdala structures.

A-40 The Neurocognitive and Behavioral Profile of an Adolescent with in-Utero Exposure to Alcohol

Abstract Objective Prenatal alcohol exposure can result in altered brain development that has detrimental effects on children and put them at increased risk for cognitive impairment, sensorimotor deficits, attention problems, behavioral issues, and social–emotional difficulties. Further, adolescents with neurodevelopmental disorders associated with in-utero exposure to alcohol require targeted academic and psychosocial support as they transition into adulthood which emphasizes the need for neuropsychological assessment. Method This case study presents on the neuropsychological profile of a 17-year-old male in the 11th grade who was exposed to alcohol in-utero and was diagnosed with fetal alcohol effects as a young child by his primary care physician. Results Neuropsychological testing revealed a broad range of impairments which included deficits in intellectual functioning (mild disability), adaptive functioning, language, academic achievement, attention, executive functioning, memory, fine/visuomotor skills, and social–emotional functioning. Conclusions Recommendations were made to modify his special education goals by targeting his functional academic skills, adaptive functioning, communication skills, and post-high school transition planning. Recommendations for behavioral interventions were given to his referring psychotherapist to aid in treatment planning. Information on vocational counseling and financial support for individuals with developmental disabilities were provided to the patient’s guardian as well. This case study illustrates the long-lasting neurocognitive and behavioral effects associated with in-utero alcohol exposure and the need for neuropsychological assessment during adolescence in order to reduce secondary issues (e.g., school problems, lack of mental health support, unemployment, and financial hardship) that can occur as these individuals move into adulthood.

Directional Persistence of Cell Migration in Schizophrenia Patient-Derived Olfactory Cells.

Cell migration is critical for brain development and linked to several neurodevelopmental disorders, including schizophrenia. We have shown previously that cell migration is dysregulated in olfactory neural stem cells from people with schizophrenia. Although they moved faster than control cells on plastic substrates, patient cells were insensitive to regulation by extracellular matrix proteins, which increase the speeds of control cells. As well as speed, cell migration is also described by directional persistence, the straightness of movement. The aim of this study was to determine whether directional persistence is dysregulated in schizophrenia patient cells and whether it is modified on extracellular matrix proteins. Directional persistence in patient-derived and control-derived olfactory cells was quantified from automated live-cell imaging of migrating cells. On plastic substrates, patient cells were more persistent than control cells, with straighter trajectories and smaller turn angles. On most extracellular matrix proteins, persistence increased in patient and control cells in a concentration-dependent manner, but patient cells remained more persistent. Patient cells therefore have a subtle but complex phenotype in migration speed and persistence on most extracellular matrix protein substrates compared to control cells. If present in the developing brain, this could lead to altered brain development in schizophrenia.

Links between socioeconomic disadvantage, neural function, and working memory in early childhood.

Children reared in socioeconomically disadvantaged environments are at risk for academic, cognitive, and behavioral problems. Mounting evidence suggests that childhood adversities, encountered at disproportionate rates in contexts of socioeconomic risk, shape the developing brain in ways that explain disparities. Circuitries that subserve neurocognitive functions related to memory, attention, and cognitive control are especially affected. However, most work showing altered neural function has focused on middle childhood and adolescence. Understanding alterations in brain development during foundational points in early childhood is a key next step. To address this gap, we examined functional near-infrared-spectroscopy-based neural activation during a working memory (WM) task in young children aged 4-7 years (N=30) who varied in socioeconomic risk exposure. Children who experienced greater disadvantage (lower income to needs ratio and lower Hollingshead index) exhibited lower activation in the lateral prefrontal cortex than children who experienced less to no disadvantage. Variability in prefrontal cortex activation, but not behavioral performance on the WM task, was associated with worse executive functioning in children as reported by parents. These findings add to existing evidence that exposure to early adversity, such as socioeconomic risk, may lead to foundational changes in the developing brain, which increases risk for disparities in functioning across multiple cognitive and social domains.

Structural and functional connectivity in premature neonates

Advances in neuroimaging have increasingly enabled researchers to investigate whether alterations in brain development commonly identified in preterm infants underlie their high risk of long-term neurodevelopmental impairment, including sensory, motor, cognitive, and psychiatric deficits. This review begins by examining the growing body of literature utilizing advanced magnetic resonance imaging (MRI) techniques to probe structural (via diffusion MRI) and functional (via resting state-functional MRI) connectivity development in the preterm brain during the neonatal period, both in the presence and absence of brain injury. It then details the recent work linking neonatal brain connectivity measures to neurodevelopmental and psychiatric outcomes in prematurely-born cohorts. Finally, building upon the recent substantive growth in the utilization of these neuroimaging modalities, it concludes by highlighting areas in which continued optimization of age-specific acquisition and analysis techniques for these data remains necessary, efforts fundamental to advancing the field toward establishing individual-level predictive capabilities in this high-risk population.

Agricultural groundwater with high nitrates and dissolved salts given to pregnant mice alters brain development in the offspring

Groundwater is the main source of drinking water for a significant portion of the human population. In many agricultural areas, diffuse pollution such as high levels of total dissolved salts including nitrate, puts the quality of this resource at risk. However, the effect of exposure to these water contaminants on brain development is currently poorly understood. Here we characterised water from a borewell located in an intensely cultivated area (agricultural) or water from a borewell located in a nearby pristine forest. The agricultural borewell water was rich in nitrates with high total dissolved salts. We then studied the consequence of drinking the agricultural water on mouse brain development. For this, the agricultural borewell water or forest water was given to mice for 6 weeks before and during pregnancy and lactation. The brains of the offspring born to these dams were analysed at postnatal day (P)5 and P21 and compared using immunohistochemistry for changes in glial cells, neurons, myelin, and cell death across many brain regions. Brains from offspring born to dams who had been given agricultural water (versus forest control water) were significantly smaller, and at P21 had a significant degeneration of neurons and increased numbers of microglia in the motor cortex, had fewer white matter astrocytes and an increase in cell death, particularly in the dentate gyrus. This study shows that brain development is sensitive to water composition. It points to the importance of assessing neurodevelopmental delays when considering the effect of water contaminated with agricultural run offs on human health. Main findingPregnant and lactating mice were given borewell water from intensely cultivated land. Offspring brains reveal degeneration of neurons and a loss of astrocytes, increase in microglial cells and cell death, pointing to neurodevelopmental problems.

Miswiring the brain: Human prenatal Δ9-tetrahydrocannabinol use associated with altered fetal hippocampal brain network connectivity

Increasing evidence supports a link between maternal prenatal cannabis use and altered neural and physiological development of the child. However, whether cannabis use relates to altered human brain development prior to birth, and specifically, whether maternal prenatal cannabis use relates to connectivity of fetal functional brain systems, remains an open question. The major objective of this study was to identify whether maternal prenatal cannabis exposure (PCE) is associated with variation in human brain hippocampal functional connectivity prior to birth. Prenatal drug toxicology and fetal fMRI data were available in a sample of 115 fetuses [43 % female; mean age 32.2 weeks (SD = 4.3)]. Voxelwise hippocampal connectivity analysis in a subset of age and sex-matched fetuses revealed that PCE was associated with alterations in fetal dorsolateral, medial and superior frontal, insula, anterior temporal, and posterior cingulate connectivity. Classification of group differences by age 5 outcomes suggest that compared to the non-PCE group, the PCE group is more likely to have increased connectivity to regions associated with less favorable outcomes and to have decreased connectivity to regions associated with more favorable outcomes. This is preliminary evidence that altered fetal neural connectome may contribute to neurobehavioral vulnerability observed in children exposed to cannabis in utero.

Alterations in the Epigenetic Landscape Underlying Later-Life Health Effects Due to In-utero Exposure to Endocrine Disrupting Chemicals: A Review of Outcomes from Mice to Men

Widespread persistence of Endocrine Disrupting Chemicals (EDCs) in the environment has mandated the need to study their potential long-term effects on human health, after acute as well aschronic exposures. The particular focus is on in utero exposure to EDCs in rodent models to look at altered epigenetic programming to result in transgenerational effects in later life of the offspring. This potentially contributes to reproductive and immune dysfunctions, obesity, cancer, and altered brain development and neurobehavioral outcomes. The literature to date establishes the transgenerational effects associated with in utero exposure to EDCs in rodent models. Hence, the aim of this review is to provide a comprehensive overview of epigenetic programming and its regulation in mammals, specially focussing on epigenetic plasticity and susceptibility to exogenous endocrine-active chemicals, EDCs, during the early developmental period, and carried forward to later life using rodent models. The available reports suggest that the key mechanism behind the long-term impact of EDCs is caused by alterations in the epigenetic programming machinery, leading to dysregulated gene expression during adult life. Studies have reported the effect of prenatal exposure to EDCs in the ovarian microRNA expression and function, highlighting ovary as an organ undergoing in utero programming. It ascertains the heightened sensitivity of the organ to exogenous hormone-active compounds, particularly during early development. In addition to this, another key aspect in this review is increased susceptibility of the brain when exposed to even minute quantities of EDCs during embryonic development, resulting in profound alterations in the structural organization of the brain and neurobehavior. Detailed analyses of variables such as folic acid and phytoestrogen content in maternal diet need to be considered as crucial factors while designing experiments and therapeutic interventions. Apart from this, appropriate animal handling during the experimental procedures to eliminate stress in animal models to ensure unbiased results is recommended.

Histamine, Neuroinflammation and Neurodevelopment: A Review.

The biogenic amine, histamine, has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders. Indeed, a reduction in the synthesis of this neuromodulator has been associated with the disorders Tourette’s syndrome and obsessive-compulsive disorder, with evidence that this may be through the disruption of the corticostriatal circuitry during development. Furthermore, neuroinflammation has been associated with alterations in brain development, e.g., impacting synaptic plasticity and synaptogenesis, and there are suggestions that histamine deficiency may leave the developing brain more vulnerable to proinflammatory insults. While most studies have focused on neuronal sources of histamine it remains unclear to what extent other (non-neuronal) sources of histamine, e.g., from mast cells and other sources, can impact brain development. The few studies that have started exploring this in vitro, and more limited in vivo, would indicate that non-neuronal released histamine and other preformed mediators can influence microglial-mediated neuroinflammation which can impact brain development. In this Review we will summarize the state of the field with regard to non-neuronal sources of histamine and its impact on both neuroinflammation and brain development in key neural circuits that underpin neurodevelopmental disorders. We will also discuss whether histamine receptor modulators have been efficacious in the treatment of neurodevelopmental disorders in both preclinical and clinical studies. This could represent an important area of future research as early modulation of histamine from neuronal as well as non-neuronal sources may provide novel therapeutic targets in these disorders.